We have found that Akt signaling contributes to some of the more notable abnormalities in tumor vascular stroma. Those vascular abnormalities include the propensity for excessive vascular permeability leading to tissue edema and sluggish blood flow, extravasation of fibrin and other matrix proteins that alter the extracellular microenvironment, and the trafficking of inflammatory cells and tumor cells in and out of the tumor-associated vasculature. In addition, we also showed that rapamycin is an effective inhibitor of Akt signaling in the tumor stroma. This grant application is designed to study rapamycin's effects on the tumor stroma and to determine the impact of the anti-stromal effects of rapamycin on its anti-tumor efficacy. Both vascular and nonvascular stroma will be studied. Aim 1 is focused on identification of the vessel and vascular molecular targets that mediate rapamycin's anti-angiogenic efficacy. Aim 2 is designed to test the importance of rapamycin stromal targets in cancer inhibition. Aim 3 investigates rapamycin inhibition tumor cell trafficking across the endothelium and metastasis. PUBLIC HEALTH RELEVANCE: This project is designed to dissect the Akt pathway inhibitor, rapamycin, in the tumor microenvironment. Rapamycin is one the most specific small molecule inhibitors inc clinical use and inhibits mTOR with subsequent feedback onto upstream signaling that results from mTOR's function as an Akt kinase. While in clinical trials for cancer, recent data suggests that it functions more effectively when administered in a metronomic fashion, and our data suggests that it is an effective inhibitor of the tumor vasculature. This application proposes to dissect the stromal cellular targets of rapamycin in breast cancer, and investigate the overall impact of those targets on rapamycin's anti tumor efficacy.